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系統識別號 U0026-2404201409184500
論文名稱(中文) 以力學觀點探討正常或癌化上皮細胞間葉化
論文名稱(英文) The Normal or Cancerous Cell Mechanical Properties Alteration After Epithelial-Mesenchymal Transition
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 102
學期 2
出版年 103
研究生(中文) 吳宗憲
研究生(英文) Tsung-Hsien Wu
學號 P88981089
學位類別 博士
語文別 英文
論文頁數 130頁
口試委員 指導教授-葉明龍
口試委員-林昭宏
口試委員-湯銘哲
口試委員-陳嘉炘
口試委員-邱文泰
口試委員-詹正雄
中文關鍵字 轉化生長因子  上皮細胞間葉化  細胞力學  腫瘤復發  肺癌轉移 
英文關鍵字 TGF-beta 1  EMT  Cell Mechanics  Tumor recurrence  Lung cancer metastasis 
學科別分類
中文摘要 上皮細胞的間葉化 (epithelial-mesenchymal transition, EMT)涉及到幾個眾所皆知的生理以及病理現象,而且能使癌症細胞擁有遷移和侵入的特性。然而,迄今間葉化過程之細胞力學改變仍未得到一致的結論,除此之外,基材軟硬與型態如何影響間葉化後細胞的爬行速度也尚待闡明。近期研究已經開始採用細胞力學區辨間葉化過程以及診斷癌症惡性分期,但在腫瘤環境中間葉化出現在癌症細胞侵入或穿出血管的時間僅僅維持數秒鐘,所以至今仍缺乏利用細胞力學預測腫瘤惡化或轉移的研究。
因此,本研究目的為二:首先,發展一套微板量測系統 (microplate measurement system, MMS),此系統利用彈性探針的偏折量去計算細胞的勁度和貼附力,提供奈米牛頓等級的力學解析度去探討間葉化過程的力學變化,同時探討間葉化前後細胞在特殊二維表面形態上的爬行特性改變,可調控的基材特性包含1微米或5微米線寬、溝槽狀或圓錐狀、軟(1.96±0.48 MPa)或硬(3.70±0.74 MPa) 之聚二甲基矽氧烷基材。第二個研究目的是藉由分析腫瘤老鼠身上取出之癌細胞力學特性,預測腫瘤復發以及轉移可能性,可以進一步建立癌症生理以及細胞力學間的關聯性。
實驗結果顯示在長時間貼附後,間葉化後細胞有勁度高貼附力強的細胞力學特性,是因為具有較粗的肌動蛋白以及豐富的貼附蛋白表現,因此微板量測系統(MMS)能區辨間葉化前後細胞力學的改變,包含:壓縮勁度(500.0和616.6 Pa)、拉伸勁度(469.3和 517.5 Pa)和黏附力(153.2和173.9 nN),一旦利用肌動(cytochalasin D)或肌凝蛋白阻斷劑(ML-7)將肌動蛋白或肌凝蛋白的合成或活化抑制,則間葉化前後的細胞力學差異將會消失。另外,間葉化之後的細胞因為α-平滑肌動蛋白與貼附蛋白高度共位性表現,所以具有較快的爬行速度,然而在2MPa的基材上間葉化後細胞會因為1微米線寬的椎狀基材效應而減速達0.13微米/分(較溝槽狀慢36%),但在5微米線寬溝槽基材的加速效應反而使得間葉化後細胞爬行速度快0.18微米/分(增加100%)。
使用微板量測系統以及免疫染色分析顯示在將復發腫瘤中的細胞有非均質性的組成,包含:軟的癌症細胞、硬的間葉化癌症細胞和內皮細胞。同樣的結果也出現在原子力學顯微鏡所作的勁度分布圖,圖中顯示將復發腫瘤具有較高且複雜的勁度分布;進一步利用流式細胞儀能確定腫瘤主要由癌症細胞所構成,體外實驗結果亦發現間葉化後癌症細胞有較高力學特性,進而觀測到將復發腫瘤內有豐富血管新生,因而產生較硬的基質以及豐富的胞泌素導致腫瘤惡化與嚴重侵襲特性產生;從腫瘤萃取出的細胞力學與腫瘤預後因子的多重相關性分析,也發現了老鼠體重成長減緩以及腫瘤重量增加和細胞力學增加以及後續腫瘤復發或轉移有相關性。
細胞在間葉化後會具有較高的勁度以及貼附力,的確會加強細胞爬行與侵襲能力,因此本系統MMS適合用於癌症診斷、藥物開發和細胞與基材效應之研究,在臨床應用方面,也可以在腫瘤切除後合併使用MMS搭配診斷,進一步預測腫瘤之復發性與轉移性。
英文摘要 The epithelial-mesenchymal transition (EMT) is known to involve several physiological and pathological phenomena and endows cells with invasive and migratory properties. However, to identify the alteration of mechanical property of cell undergoing EMT needs further elucidation. Moreover, the effects of substrate stiffness and topography on the migration of cells before or after transforming growth factor-β1 (TGF-β1)-induced EMT are unknown. The cell mechanical properties (CMs) can be used to identify not only cancer EMT, but also the cancer malignant transforming process. Previous in situ study revealed that EMT taken place and affected cancer cells in seconds during intravasation and extravasation. However, there is a scarcity of defined tumor CMs with which to predict which noninvasive tumors will progress to malignancy and which cancers will metastasize.
Therefore, there were two purposes in this study. Firstly, this study utilized a microplate measurement system (MMS) approach based on the deflection of a flexible micro-cantilever was built to measure cell stiffness (in Pa) and adhesion force (in nN) of a single cell during EMT with nN resolution. Herein, the migration alteration of EMT cell model were measured on the 2D patterns consisted of 1 μm or 5 μm line-widths and groove or cone patterns on either soft (1.96±0.48 MPa) or stiff (3.70±0.74 MPa) polydimethylsiloxane (PDMS) substrates. Secondly, in bridging across physical and physiological disciplines, this study reconciled single-cell measurements in whether recurrent or not tumors and reveal CMs can be used to predict cancer malignant transformation.
The results demonstrated that after EMT, mesenchymal cells became stiffer due to thicker and more abundant F-actin and displayed stronger vinculin accumulation after long-term cell-substrate adhesion. The MMS could distinguish differences in compressive stiffness (500.0 and 616.6 Pa), tensile stiffness (469.3 and 517.5 Pa), and adhesion force (153.2 and 173.9 nN) between cells before and after EMT. However, without proper development of the F-actin or myosin II structure following cytochalasin D (cyto-D) or ML-7 inhibition, the mechanical differences were diminished.
The increased expression of α-smooth muscle actin (α-SMA) with vinculin in focal adhesion (FA) sites led to an acceleration of EMT cell motility. On the 2 MPa substrate, the most influenced substrate was the 1 μm, cone-patterned substrate, where the EMT cells motility decelerated by 0.13 μm/min (36% slower than the cells on groove pattern). However, on the 5 μm, groove-patterned substrate, where the EMT cells demonstrated the most rapid motility relative to the control cells, with a increment of 0.18 μm/min (100%).
Using MMS combined immunostaining, the discrete results demonstrated the intrinsic heterogeneous composition of Rec tumor: including soft lewis lung cancer cell (LLC), stiff EMT LLC and endothelial cells. Also, using atomic force microscopy (AFM) force mapping, the identified stiffer and more complex composition in Rec tumors were observed. By flowcytometry differentiation, the tumor-retrieval cells were mainly identified as LLC. In vitro experiment showed LLC acquired stiffer properties after EMT as well. Additionally, the rich angiogenesis in Rec tumors offer the stiffer stroma and cytokines for tumor malignant transformation and aggressive invasion ability. A comprehensive effort to correlate the CMs of tumor-retrieval cells to specific tumor-prognosis markers were conducted in this study. Trivially, the decreased body weight gain ratio (BWG) and increased tumor weight (TW) correlated with the stiffer and adhesive CMs of tumors as well as the recurrence and metastasis possibility.
After EMT, the cells with increased stiffness and cell-substrate adhesion force were benefited by faster migratiion and higher invasiveness. Thus, this technology has the potential to benefit researches on cancer diagnosis, drug development, and cell-substrate interactions. In terms of clinical application, the local tumor excision followed by MMS analysis offer the predictability of tumor recurrence and metastasis.
論文目次 Table of contents
中文摘要 I
Abstract III
致謝 VI
Table list XI
Figure list XII
Glossary of Abbreviations XIV
Chapter 1: Introduction 1
1.1 Epithelial-mesenchymal transition (EMT) 1
1.2 Cell mechanics and mechanical measurement tools 4
1.3 Cell-mechanic measurement tools comparison 7
1.4 Cell migration alteration after EMT 11
1.5 Tumor-retrieval-cell mechanical properties 13
1.6 Purpose and specific aims Part I (epithelial cell study): 14
Chapter 2: Materials and Methods 15
2.1 Flow chart of experiment 15
2.1.1 Part I: In vitro epithelial cell EMT study 15
2.1.2 Part II: Animal study (tumor-bearing mice model) 17
2.2 Part I: In vitro epithelial cell EMT study 18
2.2.1 TGF-β1-induced EMT model 18
2.2.2 Reagents and inhibitors 18
2.2.3 Cell-proliferation assay 18
2.2.4 Immunofluorescence staining 19
2.2.5 Cell height and spreading area topography scanning by AFM 19
2.2.6 Experimental setup of microplate measurement system (MMS) 19
2.2.7 Image analysis and mechanical properties estimation 24
2.2.8 Fabrication of silicon wafer mold 25
2.2.9 PDMS substrate preparation 26
2.2.10 Topography of substrate and cell morphology 26
2.2.11 Time-lapse cell migration analysis 27
2.2.12 Image analysis of migration behavior 27
2.2.13 Wound healing assay 27
2.2.14 Invasion assay 28
2.3 Part II: Animal study: tumor-bearing mice model 29
2.3.1 Xenograft mouse model and ex vivo tumor-retrieved cells. 29
2.3.2. Flowcytometry selection 30
2.3.3. Tumor prognosis factors evaluation 30
2.3.4. Immunofluorescence and immunohistochemistry staining 31
2.3.5. ELISA for TGF-β1 in culture medium 32
2.3.6. Western blot for E-cadherin expression 32
2.3.7. Tumor-retrieval cells invasion assay 32
2.3.8. AFM identified stiffness-composition of tumors 33
2.4 Statistical analysis 33
Chapter 3: Results 35
3.1 Part I: In vitro TGF-β1 induced EMT experiment 35
3.1.1 Differentiation the effect of EMT on NMuMG cell 35
3.1.2 Cell mechanical properties alteration after TGF-β1 and addition of inhibitor 37
3.1.3. Effects of ML-7 on F-actin, vinculin and cell-ECM adhesion force 41
3.1.4. The effect of EMT on cell migration and invasion behaviors 45
3.1.5. TGF-β1-induced cell-type shifts result in combined substrate topography and stiffness effects on migration speed 47
3.1.6. Differences in stiffness and line-widths of groove-patterned substrates influence migration directionality 50
3.1.7. Combined physical and TGF-β1 effects 51
3.1.8. Combined physical and TGF-β1 effects on cell shapes, orientations and spreading morphology 52
3.2 Part II: Animal study: tumor-bearing mice model 55
3.2.1. Tumor retrieval CMs 55
3.2.2. Flow cytometry identification of tumor-retrieved cells 61
3.2.3. AFM measured stiffness 63
3.2.4. Assessment of tumor malignancy 64
3.2.5. In vitro treatment with SB-505124 abrogates TGF-β1-induced EMT and changes in E-cadherin expression, cell motility and cell mechanics 66
3.2.6. Metastatic and invasive abilities of tumor-retrieved cells 68
3.2.7. Association between CMs and tumor prognosis indicators 69
Chapter 4: Discussion 72
4.1. Part I: In vitro TGF-β1 induced EMT experiment 72
4.1.1. The F-actin and adherence-dependent mechanical differentiation of normal epithelial cells after TGF-β1-induced EMT using a microplate measurement system 72
4.1.2. Migration speed and directionality switch of normal epithelial cells after TGF-β1-induced EMT on micro-structured polydimethylsiloxane (PDMS) substrates with variations in stiffness and topographic patterning 77
4.2. Part II: Animal study: tumor-bearing mice model 84
4.2.1. Flow cytometry identification of tumor-retrieved cells 84
4.2.2. Tumor retrieval CMs 85
4.2.3. AFM measurements of stiffness 87
4.2.4. Assessment of tumor malignancy 89
4.2.5. In vitro treatment with SB-505124 abrogates TGF-β1-induced EMT and changes in E-cadherin expression, cell motility, and cell mechanics 91
4.2.6. Metastatic and invasive abilities of the tumor-retrieved cells 92
4.2.7. Association between CMs and tumor prognosis indicators 93
Chapter 5: Conclusion 94
Chapter 6: Limitations and future works 97
References 101
Curriculum vitae 127
參考文獻 References
1. Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation 2003, 112(12):1776-1784.
2. Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nature reviews Molecular cell biology 2006, 7(2):131-142.
3. Labelle M, Begum S, Hynes RO: Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011, 20(5):576-590.
4. Birchmeier W: Cell adhesion and signal transduction in cancer. Conference on cadherins, catenins and cancer. EMBO Rep 2005, 6(5):413-417.
5. Buergy D, Wenz F, Groden C, Brockmann MA: Tumor-platelet interaction in solid tumors. Int J Cancer 2012, 130(12):2747-2760.
6. Tzvetkova-Chevolleau T, Stephanou A, Fuard D, Ohayon J, Schiavone P, Tracqui P: The motility of normal and cancer cells in response to the combined influence of the substrate rigidity and anisotropic microstructure. Biomaterials 2008, 29(10):1541-1551.
7. Kalluri R, Weinberg RA: The basics of epithelial-mesenchymal transition. The Journal of clinical investigation 2009, 119(6):1420-1428.
8. Thiery JP, Acloque H, Huang RYJ, Nieto MA: Epithelial-Mesenchymal Transitions in Development and Disease. Cell 2009, 139(5):871-890.
9. Miettinen PJ, Ebner R, Lopez AR, Derynck R: TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994, 127(6 Pt 2):2021-2036.
10. Rastaldi MP, Ferrario F, Giardino L, Dell'Antonio G, Grillo C, Grillo P, Strutz F, Muller GA, Colasanti G, D'Amico G: Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 2002, 62(1):137-146.
11. Zavadil J, Bottinger EP: TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005, 24(37):5764-5774.
12. Beach JR, Hussey GS, Miller TE, Chaudhury A, Patel P, Monslow J, Zheng Q, Keri RA, Reizes O, Bresnick AR et al: Myosin II isoform switching mediates invasiveness after TGF-beta-induced epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 2011, 108(44):17991-17996.
13. Mori M, Nakagami H, Koibuchi N, Miura K, Takami Y, Koriyama H, Hayashi H, Sabe H, Mochizuki N, Morishita R et al: Zyxin mediates actin fiber reorganization in epithelial-mesenchymal transition and contributes to endocardial morphogenesis. Mol Biol Cell 2009, 20(13):3115-3124.
14. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133(4):704-715.
15. Thoelking G, Reiss B, Wegener J, Oberleithner H, Pavenstaedt H, Riethmuller C: Nanotopography follows force in TGF-beta1 stimulated epithelium. Nanotechnology 2010, 21(26):265102.
16. Suresh S: Biomechanics and biophysics of cancer cells. Acta Biomater 2007, 3(4):413-438.
17. Suresh S: Nanomedicine: elastic clues in cancer detection. Nat Nanotechnol 2007, 2(12):748-749.
18. Buckley ST, Medina C, Davies AM, Ehrhardt C: Cytoskeletal re-arrangement in TGF-beta1-induced alveolar epithelial-mesenchymal transition studied by atomic force microscopy and high-content analysis. Nanomedicine 2012, 8(3):355-364.
19. Lam WA, Rosenbluth MJ, Fletcher DA: Increased leukaemia cell stiffness is associated with symptoms of leucostasis in paediatric acute lymphoblastic leukaemia. Br J Haematol 2008, 142(3):497-501.
20. Swaminathan V, Mythreye K, O'Brien ET, Berchuck A, Blobe GC, Superfine R: Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res 2011, 71(15):5075-5080.
21. Dardik R, Kaufmann Y, Savion N, Rosenberg N, Shenkman B, Varon D: Platelets mediate tumor cell adhesion to the subendothelium under flow conditions: involvement of platelet GPIIb-IIIa and tumor cell alpha(v) integrins. Int J Cancer 1997, 70(2):201-207.
22. Li Y, Yang K, Mao Q, Zheng X, Kong D, Xie L: Inhibition of TGF-beta receptor I by siRNA suppresses the motility and invasiveness of T24 bladder cancer cells via modulation of integrins and matrix metalloproteinase. Int Urol Nephrol 2010, 42(2):315-323.
23. Wei YY, Chen YJ, Hsiao YC, Huang YC, Lai TH, Tang CH: Osteoblasts-derived TGF-beta1 enhance motility and integrin upregulation through Akt, ERK, and NF-kappaB-dependent pathway in human breast cancer cells. Mol Carcinog 2008, 47(7):526-537.
24. Docheva D, Padula D, Schieker M, Clausen-Schaumann H: Effect of collagen I and fibronectin on the adhesion, elasticity and cytoskeletal organization of prostate cancer cells. Biochem Biophys Res Commun 2010, 402(2):361-366.
25. Wu CC, Su HW, Lee CC, Tang MJ, Su FC: Quantitative measurement of changes in adhesion force involving focal adhesion kinase during cell attachment, spread, and migration. Biochem Biophys Res Commun 2005, 329(1):256-265.
26. Colbert MJ, Brochard-Wyart F, Fradin C, Dalnoki-Veress K: Squeezing and detachment of living cells. Biophys J 2010, 99(11):3555-3562.
27. Thoumine O, Ott A, Louvard D: Critical centrifugal forces induce adhesion rupture or structural reorganization in cultured cells. Cell Motil Cytoskeleton 1996, 33(4):276-287.
28. Lee J, Leonard M, Oliver T, Ishihara A, Jacobson K: Traction forces generated by locomoting keratocytes. J Cell Biol 1994, 127(6 Pt 2):1957-1964.
29. Chen J, Li H, SundarRaj N, Wang JH: Alpha-smooth muscle actin expression enhances cell traction force. Cell Motil Cytoskeleton 2007, 64(4):248-257.
30. Tseng Q, Wang I, Duchemin-Pelletier E, Azioune A, Carpi N, Gao J, Filhol O, Piel M, Thery M, Balland M: A new micropatterning method of soft substrates reveals that different tumorigenic signals can promote or reduce cell contraction levels. Lab Chip, 11(13):2231-2240.
31. Zhang HJ, Wang HY, Zhang HT, Su JM, Zhu J, Wang HB, Zhou WY, Zhang H, Zhao MC, Zhang L et al: Transforming growth factor-beta1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. Mol Cell Biochem, 355(1-2):309-314.
32. Colbert MJ, Raegen AN, Fradin C, Dalnoki-Veress K: Adhesion and membrane tension of single vesicles and living cells using a micropipette-based technique. Eur Phys J E Soft Matter 2009, 30(2):117-121.
33. Miyazaki H, Hasegawa Y, Hayashi K: A newly designed tensile tester for cells and its application to fibroblasts. J Biomech 2000, 33(1):97-104.
34. Chu YS, Thomas WA, Eder O, Pincet F, Perez E, Thiery JP, Dufour S: Force measurements in E-cadherin-mediated cell doublets reveal rapid adhesion strengthened by actin cytoskeleton remodeling through Rac and Cdc42. J Cell Biol 2004, 167(6):1183-1194.
35. Friedrichs J, Helenius J, Muller DJ: Stimulated single-cell force spectroscopy to quantify cell adhesion receptor crosstalk. Proteomics 2010, 10(7):1455-1462.
36. Yamamoto A, Mishima S, Maruyama N, Sumita M: Quantitative evaluation of cell attachment to glass, polystyrene, and fibronectin- or collagen-coated polystyrene by measurement of cell adhesive shear force and cell detachment energy. J Biomed Mater Res 2000, 50(2):114-124.
37. Bates RC, Bellovin DI, Brown C, Maynard E, Wu BY, Kawakatsu H, Sheppard D, Oettgen P, Mercurio AM: Transcriptional activation of integrin beta 6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 2005, 115(2):339-347.
38. Stewart MP, Helenius J, Toyoda Y, Ramanathan SP, Muller DJ, Hyman AA: Hydrostatic pressure and the actomyosin cortex drive mitotic cell rounding. Nature 2011, 469(7329):226-230.
39. Shen Y, Nakajima M, Kojima S, Homma M, Fukuda T: Study of the time effect on the strength of cell-cell adhesion force by a novel nano-picker. Biochem Biophys Res Commun, 409(2):160-165.
40. Matsui TS, Deguchi S, Sakamoto N, Ohashi T, Sato M: A versatile micro-mechanical tester for actin stress fibers isolated from cells. Biorheology 2009, 46(5):401-415.
41. Itabashi T, Takagi J, Shimamoto Y, Onoe H, Kuwana K, Shimoyama I, Gaetz J, Kapoor TM, Ishiwata S: Probing the mechanical architecture of the vertebrate meiotic spindle. Nat Methods 2009, 6(2):167-172.
42. Mitrossilis D, Fouchard J, Guiroy A, Desprat N, Rodriguez N, Fabry B, Asnacios A: Single-cell response to stiffness exhibits muscle-like behavior. Proc Natl Acad Sci U S A 2009, 106(43):18243-18248.
43. Guilak F, Mow VC: The mechanical environment of the chondrocyte: a biphasic finite element model of cell-matrix interactions in articular cartilage. J Biomech 2000, 33(12):1663-1673.
44. Sellers JR: Regulation of cytoplasmic and smooth muscle myosin. Curr Opin Cell Biol 1991, 3(1):98-104.
45. Endow SA, Titus MA: Genetic approaches to molecular motors. Annu Rev Cell Biol 1992, 8:29-66.
46. Cooper JA: The role of actin polymerization in cell motility. Annu Rev Physiol 1991, 53:585-605.
47. Isemura M, Mita T, Satoh K, Narumi K, Motomiya M: Myosin light chain kinase inhibitors ML-7 and ML-9 inhibit mouse lung carcinoma cell attachment to the fibronectin substratum. Cell Biol Int Rep 1991, 15(10):965-972.
48. Gillespie GY, Soroceanu L, Manning TJ, Jr., Gladson CL, Rosenfeld SS: Glioma migration can be blocked by nontoxic inhibitors of myosin II. Cancer Res 1999, 59(9):2076-2082.
49. Li H, Cook JD, Terry M, Spitzer NC, Ferrari MB: Calcium transients regulate patterned actin assembly during myofibrillogenesis. Dev Dyn 2004, 229(2):231-242.
50. Rotsch C, Radmacher M: Drug-induced changes of cytoskeletal structure and mechanics in fibroblasts: An atomic force microscopy study. Biophysical Journal 2000, 78(1):520-535.
51. Martens JC, Radmacher M: Softening of the actin cytoskeleton by inhibition of myosin II. Pflugers Archiv-European Journal of Physiology 2008, 456(1):95-100.
52. Straight AF, Cheung A, Limouze J, Chen I, Westwood NJ, Sellers JR, Mitchison TJ: Dissecting temporal and spatial control of cytokinesis with a myosin II Inhibitor. Science 2003, 299(5613):1743-1747.
53. Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I, Mahalu D, Safran S, Bershadsky A, Addadi L et al: Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol 2001, 3(5):466-472.
54. Grashoff C, Hoffman BD, Brenner MD, Zhou R, Parsons M, Yang MT, McLean MA, Sligar SG, Chen CS, Ha T et al: Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature, 466(7303):263-266.
55. Humphries JD, Wang P, Streuli C, Geiger B, Humphries MJ, Ballestrem C: Vinculin controls focal adhesion formation by direct interactions with talin and actin. J Cell Biol 2007, 179(5):1043-1057.
56. Nagayama K, Yanagihara S, Matsumoto T: A novel micro tensile tester with feed-back control for viscoelastic analysis of single isolated smooth muscle cells. Med Eng Phys 2007, 29(5):620-628.
57. Ofek G, Wiltz DC, Athanasiou KA: Contribution of the cytoskeleton to the compressive properties and recovery behavior of single cells. Biophys J 2009, 97(7):1873-1882.
58. Colbert MJ, Brochard-Wyart F, Fradin C, Dalnoki-Veress K: Squeezing and detachment of living cells. Biophys J, 99(11):3555-3562.
59. Mitrossilis D, Fouchard J, Pereira D, Postic F, Richert A, Saint-Jean M, Asnacios A: Real-time single-cell response to stiffness. Proc Natl Acad Sci U S A, 107(38):16518-16523.
60. Cross SE, Jin YS, Tondre J, Wong R, Rao J, Gimzewski JK: AFM-based analysis of human metastatic cancer cells. Nanotechnology 2008, 19(38):384003.
61. Cross SE, Jin YS, Lu QY, Rao J, Gimzewski JK: Green tea extract selectively targets nanomechanics of live metastatic cancer cells. Nanotechnology, 22(21):215101.
62. Buckley ST, Medina C, Davies AM, Ehrhardt C: Cytoskeletal re-arrangement in TGF-beta1-induced alveolar epithelial-mesenchymal transition studied by atomic force microscopy and high-content analysis. Nanomedicine, 8(3):355-364.
63. Lekka M, Laidler P: Applicability of AFM in cancer detection. Nat Nanotechnol 2009, 4(2):72; author reply 72-73.
64. Shen Y, Nakajima M, Kojima S, Homma M, Fukuda T: Study of the time effect on the strength of cell-cell adhesion force by a novel nano-picker. Biochem Biophys Res Commun 2011, 409(2):160-165.
65. Lamouille S, Derynck R: Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007, 178(3):437-451.
66. Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP: Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci U S A 2001, 98(12):6686-6691.
67. Kabashima A, Higuchi H, Takaishi H, Matsuzaki Y, Suzuki S, Izumiya M, Iizuka H, Sakai G, Hozawa S, Azuma T et al: Side population of pancreatic cancer cells predominates in TGF-beta-mediated epithelial to mesenchymal transition and invasion. Int J Cancer 2009, 124(12):2771-2779.
68. Kaneko K, Satoh K, Masamune A, Satoh A, Shimosegawa T: Myosin light chain kinase inhibitors can block invasion and adhesion of human pancreatic cancer cell lines. Pancreas 2002, 24(1):34-41.
69. Friedl P, Wolf K: Plasticity of cell migration: a multiscale tuning model. The Journal of cell biology 2010, 188(1):11-19.
70. Clark P, Connolly P, Curtis AS, Dow JA, Wilkinson CD: Topographical control of cell behaviour: II. Multiple grooved substrata. Development 1990, 108(4):635-644.
71. Lim JY, Donahue HJ: Cell sensing and response to micro- and nanostructured surfaces produced by chemical and topographic patterning. Tissue engineering 2007, 13(8):1879-1891.
72. Wilkinson CDW, Riehle M, Wood M, Gallagher J, Curtis ASG: The use of materials patterned on a nano- and micro-metric scale in cellular engineering. Materials Science and Engineering: C 2002, 19(1–2):263-269.
73. Chen C-C, Hsieh PC-H, Wang G-M, Chen W-C, Yeh M-L: The influence of surface morphology and rigidity of the substrata on cell motility. Materials Letters 2009, 63(21):1872-1875.
74. Ng MR, Besser A, Danuser G, Brugge JS: Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. J Cell Biol, 199(3):545-563.
75. Doyle AD, Kutys ML, Conti MA, Matsumoto K, Adelstein RS, Yamada KM: Micro-environmental control of cell migration--myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics. Journal of cell science, 125(Pt 9):2244-2256.
76. Berry CC, Campbell G, Spadiccino A, Robertson M, Curtis AS: The influence of microscale topography on fibroblast attachment and motility. Biomaterials 2004, 25(26):5781-5788.
77. Brunette DM: Spreading and orientation of epithelial cells on grooved substrata. Exp Cell Res 1986, 167(1):203-217.
78. Choi CH, Hagvall SH, Wu BM, Dunn JC, Beygui RE, CJ CJK: Cell interaction with three-dimensional sharp-tip nanotopography. Biomaterials 2007, 28(9):1672-1679.
79. Frey MT, Tsai IY, Russell TP, Hanks SK, Wang YL: Cellular responses to substrate topography: role of myosin II and focal adhesion kinase. Biophys J 2006, 90(10):3774-3782.
80. Miyoshi H, Ju J, Lee SM, Cho DJ, Ko JS, Yamagata Y, Adachi T: Control of highly migratory cells by microstructured surface based on transient change in cell behavior. Biomaterials 2010, 31(33):8539-8545.
81. Wójciak-Stothard B, Madeja Z, Korohoda W, Curtis A, Wilkinson C: Activation of macrophage-like cells by multiple grooved substrata. Topographical control of cell behaviour. Cell biology international 1995, 19(6):485-490.
82. Baac H, Lee JH, Seo JM, Park TH, Chung H, Lee SD, Kim SJ: Submicron-scale topographical control of cell growth using holographic surface relief grating. Materials Science and Engineering: C 2004, 24(1):209-212.
83. Dalby MJ, Riehle MO, Sutherland DS, Agheli H, Curtis ASG: Changes in fibroblast morphology in response to nano-columns produced by colloidal lithography. Biomaterials 2004, 25(23):5415-5422.
84. Miyoshi H, Adachi T, Ju J, Lee SM, Cho DJ, Ko JS, Uchida G, Yamagata Y: Characteristics of motility-based filtering of adherent cells on microgrooved surfaces. Biomaterials 2012, 33(2):395-401.
85. Yim EK, Darling EM, Kulangara K, Guilak F, Leong KW: Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of human mesenchymal stem cells. Biomaterials 2010, 31(6):1299-1306.
86. Lo CM, Wang HB, Dembo M, Wang YL: Cell movement is guided by the rigidity of the substrate. Biophysical journal 2000, 79(1):144-152.
87. Oakes PW, Patel DC, Morin NA, Zitterbart DP, Fabry B, Reichner JS, Tang JX: Neutrophil morphology and migration are affected by substrate elasticity. Blood 2009, 114(7):1387-1395.
88. Butcher DT, Alliston T, Weaver VM: A tense situation: forcing tumour progression. Nat Rev Cancer 2009, 9(2):108-122.
89. Engler AJ, Griffin MA, Sen S, Bönnemann CG, Sweeney HL, Discher DE: Myotubes Differentiate Optimally on Substrates with Tissue-Like Stiffness: Pathological Implications for Soft or Stiff Microenvironments. The Journal of Cell Biology 2004, 166(6):877-887.
90. Teixeira AI, Abrams GA, Bertics PJ, Murphy CJ, Nealey PF: Epithelial contact guidance on well-defined micro- and nanostructured substrates. J Cell Sci 2003, 116(Pt 10):1881-1892.
91. Friedl P, Brocker EB, Zanker KS: Integrins, cell matrix interactions and cell migration strategies: fundamental differences in leukocytes and tumor cells. Cell Adhes Commun 1998, 6(2-3):225-236.
92. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012, 62(1):10-29.
93. Zhang HJ, Wang HY, Zhang HT, Su JM, Zhu J, Wang HB, Zhou WY, Zhang H, Zhao MC, Zhang L et al: Transforming growth factor-beta1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. Mol Cell Biochem 2011, 355(1-2):309-314.
94. Garcia-Aguilar J, Mellgren A, Sirivongs P, Buie D, Madoff RD, Rothenberger DA: Local excision of rectal cancer without adjuvant therapy: a word of caution. Ann Surg 2000, 231(3):345-351.
95. Lock MR, Ritchie JK, Hawley PR: Reappraisal of radical local excision for carcinoma of the rectum. Br J Surg 1993, 80(7):928-929.
96. Killingback M: Local excision of carcinoma of the rectum: indications. World J Surg 1992, 16(3):437-446.
97. Inoue K, Yamamoto R, Nishiyama N, Hori T, Miyamoto Y, Takehara S, Kaji M, Kin T, Katoh T, Iwata T et al: Examination of prognostic factors after resection of pulmonary metastasis of osteosarcoma by multivariate analysis. Osaka City Med J 1998, 44(1):35-42.
98. Canetta E, Duperray A, Leyrat A, Verdier C: Measuring cell viscoelastic properties using a force-spectrometer: influence of protein-cytoplasm interactions. Biorheology 2005, 42(5):321-333.
99. Chen C-C, Hsieh PC-H, Wang G-M, Chen W-C, Yeh M-L: The Influence of Surface Morphology and Stiffness of the Substrata on Cell Motility. Mater Let 2009.
100. Lee MJ, Kim J, Lee KI, Shin JM, Chae JI, Chung HM: Enhancement of wound healing by secretory factors of endothelial precursor cells derived from human embryonic stem cells. Cytotherapy, 13(2):165-178.
101. Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, McEwan RN: A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 1987, 47(12):3239-3245.
102. DaCosta Byfield S, Major C, Laping NJ, Roberts AB: SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2004, 65(3):744-752.
103. Standiford TJ, Kuick R, Bhan U, Chen J, Newstead M, Keshamouni VG: TGF-beta-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth. Oncogene 2011, 30(21):2475-2484.
104. Zigrino P, Kuhn I, Bauerle T, Zamek J, Fox JW, Neumann S, Licht A, Schorpp-Kistner M, Angel P, Mauch C: Stromal expression of MMP-13 is required for melanoma invasion and metastasis. J Invest Dermatol 2009, 129(11):2686-2693.
105. Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K: Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Res 2009, 69(7):2783-2791.
106. Dong QG, Bernasconi S, Lostaglio S, De Calmanovici RW, Martin-Padura I, Breviario F, Garlanda C, Ramponi S, Mantovani A, Vecchi A: A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler Thromb Vasc Biol 1997, 17(8):1599-1604.
107. Katz E, Skorecki K, Tzukerman M: Niche-dependent tumorigenic capacity of malignant ovarian ascites-derived cancer cell subpopulations. Clin Cancer Res 2009, 15(1):70-80.
108. Euhus DM, Hudd C, LaRegina MC, Johnson FE: Tumor measurement in the nude mouse. J Surg Oncol 1986, 31(4):229-234.
109. Hartenstein B, Dittrich BT, Stickens D, Heyer B, Vu TH, Teurich S, Schorpp-Kistner M, Werb Z, Angel P: Epidermal development and wound healing in matrix metalloproteinase 13-deficient mice. J Invest Dermatol 2006, 126(2):486-496.
110. Weidner N: Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat 1995, 36(2):169-180.
111. Lopez JI, Kang I, You WK, McDonald DM, Weaver VM: In situ force mapping of mammary gland transformation. Integr Biol (Camb) 2011, 3(9):910-921.
112. Colton T: Statistics in Medicine. Boston, Mass: Little, Brown and Co; 1974.
113. Li F, Redick SD, Erickson HP, Moy VT: Force measurements of the alpha5beta1 integrin-fibronectin interaction. Biophys J 2003, 84(2 Pt 1):1252-1262.
114. Mori M, Nakagami H, Koibuchi N, Miura K, Takami Y, Koriyama H, Hayashi H, Sabe H, Mochizuki N, Morishita R et al: Zyxin mediates actin fiber reorganization in epithelial-mesenchymal transition and contributes to endocardial morphogenesis. Mol Biol Cell 2009, 20(13):3115-3124.
115. Luo T, Mohan K, Srivastava V, Ren Y, Iglesias PA, Robinson DN: Understanding the cooperative interaction between myosin II and actin cross-linkers mediated by actin filaments during mechanosensation. Biophys J, 102(2):238-247.
116. Willis BC, Borok Z: TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 2007, 293(3):L525-534.
117. Lehembre F, Yilmaz M, Wicki A, Schomber T, Strittmatter K, Ziegler D, Kren A, Went P, Derksen PWB, Berns A et al: NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. Embo Journal 2008, 27(19):2603-2615.
118. Lee JM, Dedhar S, Kalluri R, Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. Journal of Cell Biology 2006, 172(7):973-981.
119. Vichare S, Inamdar MM, Sen S: Influence of cell spreading and contractility on stiffness measurements using AFM. Soft Matter 2012, 8(40):10464-10471.
120. Solon J, Levental I, Sengupta K, Georges PC, Janmey PA: Fibroblast adaptation and stiffness matching to soft elastic substrates. Biophysical Journal 2007, 93(12):4453-4461.
121. Starr DA, Han M: ANChors away: an actin based mechanism of nuclear positioning. J Cell Sci 2003, 116(Pt 2):211-216.
122. Wang N, Tytell JD, Ingber DE: Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol 2009, 10(1):75-82.
123. Vichare S, Inamdar MM, Sen S: Influence of cell spreading and contractility on stiffness measurements using AFM. Soft Matter 2012.
124. Chaudhuri O, Parekh SH, Lam WA, Fletcher DA: Combined atomic force microscopy and side-view optical imaging for mechanical studies of cells. Nat Methods 2009, 6(5):383-387.
125. Kim DH, Khatau SB, Feng Y, Walcott S, Sun SX, Longmore GD, Wirtz D: Actin cap associated focal adhesions and their distinct role in cellular mechanosensing. Sci Rep 2012, 2:555.
126. Theveneau E, Mayor R: Cadherins in collective cell migration of mesenchymal cells. Current Opinion in Cell Biology 2012, 24(5):677-684.
127. Arboleda-Estudillo Y, Krieg M, Stuhmer J, Licata NA, Muller DJ, Heisenberg CP: Movement Directionality in Collective Migration of Germ Layer Progenitors. Current Biology 2010, 20(2):161-169.
128. Carmona-Fontaine C, Matthews HK, Kuriyama S, Moreno M, Dunn GA, Parsons M, Stern CD, Mayor R: Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 2008, 456(7224):957-961.
129. Wolfenson H, Bershadsky A, Henis YI, Geiger B: Actomyosin-generated tension controls the molecular kinetics of focal adhesions. J Cell Sci 2011, 124(Pt 9):1425-1432.
130. Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer 2002, 2(6):442-454.
131. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E: Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 2009, 11(11):1287-1296.
132. Schoenwaelder SM, Burridge K: Bidirectional signaling between the cytoskeleton and integrins. Curr Opin Cell Biol 1999, 11(2):274-286.
133. Small JV, Rottner K, Kaverina I, Anderson KI: Assembling an actin cytoskeleton for cell attachment and movement. Biochim Biophys Acta 1998, 1404(3):271-281.
134. Doyle AD, Kutys ML, Conti MA, Matsumoto K, Adelstein RS, Yamada KM: Micro-environmental control of cell migration--myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics. J Cell Sci 2012, 125(Pt 9):2244-2256.
135. LaGamba D, Nawshad A, Hay ED: Microarray analysis of gene expression during epithelial-mesenchymal transformation. Dev Dyn 2005, 234(1):132-142.
136. Kass L, Erler JT, Dembo M, Weaver VM: Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis. International Journal of Biochemistry & Cell Biology 2007, 39(11):1987-1994.
137. Cox TR, Erler JT: Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech 2011, 4(2):165-178.
138. Coleman RE, Rubens RD: The clinical course of bone metastases from breast cancer. Br J Cancer 1987, 55(1):61-66.
139. Suva LJ, Griffin RJ, Makhoul I: Mechanisms of bone metastases of breast cancer. Endocr Relat Cancer 2009, 16(3):703-713.
140. Wong GS, Rustgi AK: Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer 2013, 108(4):755-761.
141. Zeisberg M, Neilson EG: Biomarkers for epithelial-mesenchymal transitions. The Journal of clinical investigation 2009, 119(6):1429-1437.
142. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W et al: Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139(5):891-906.
143. Provenzano PP, Keely PJ: The role of focal adhesion kinase in tumor initiation and progression. Cell Adh Migr 2009, 3(4):347-350.
144. Klominek J, Robert KH, Sundqvist KG: Chemotaxis and Haptotaxis of Human-Malignant Mesothelioma Cells - Effects of Fibronectin, Laminin, Type-Iv Collagen, and an Autocrine Motility Factor-Like Substance. Cancer Research 1993, 53(18):4376-4382.
145. Boukhalfa G, Desmouliere A, Rondeau E, Gabbiani G, Sraer JD: Relationship between alpha-smooth muscle actin expression and fibrotic changes in human kidney. Exp Nephrol 1996, 4(4):241-247.
146. Mierke CT, Kollmannsberger P, Zitterbart DP, Smith J, Fabry B, Goldmann WH: Mechano-coupling and regulation of contractility by the vinculin tail domain. Biophysical journal 2008, 94(2):661-670.
147. Huttenlocher A, Ginsberg MH, Horwitz AF: Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity. J Cell Biol 1996, 134(6):1551-1562.
148. Schober M, Raghavan S, Nikolova M, Polak L, Pasolli HA, Beggs HE, Reichardt LF, Fuchs E: Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics. J Cell Biol 2007, 176(5):667-680.
149. Gupton SL, Waterman-Storer CM: Spatiotemporal feedback between actomyosin and focal-adhesion systems optimizes rapid cell migration. Cell 2006, 125(7):1361-1374.
150. Kim DH, Wirtz D: Focal adhesion size uniquely predicts cell migration. FASEB J 2013, 27(4):1351-1361.
151. Gallant ND, Michael KE, Garcia AJ: Cell adhesion strengthening: contributions of adhesive area, integrin binding, and focal adhesion assembly. Mol Biol Cell 2005, 16(9):4329-4340.
152. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G: Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. The Journal of cell biology 1993, 122(1):103-111.
153. Ronnov-Jessen L, Petersen OW: Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 1993, 68(6):696-707.
154. Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G: The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol 1998, 142(3):873-881.
155. Masszi A, Di Ciano C, Sirokmány G, Arthur WT, Rotstein OD, Wang J, McCulloch CAG, Rosivall L, Mucsi I, Kapus A: Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial-mesenchymal transition. American Journal of Physiology - Renal Physiology 2003, 284(5):F911-F924.
156. McCain ML, Lee H, Aratyn-Schaus Y, Kleber AG, Parker KK: Cooperative coupling of cell-matrix and cell-cell adhesions in cardiac muscle. Proc Natl Acad Sci U S A 2012, 109(25):9881-9886.
157. Abercrombie M, Dunn GA: Adhesions of fibroblasts to substratum during contact inhibition observed by interference reflection microscopy. Experimental cell research 1975, 92(1):57-62.
158. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA: Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell motility and the cytoskeleton 2005, 60(1):24-34.
159. Ronnov-Jessen L, Petersen OW: A function for filamentous alpha-smooth muscle actin: retardation of motility in fibroblasts. J Cell Biol 1996, 134(1):67-80.
160. Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL: Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 2004, 6(5):603-610.
161. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP: Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004, 23(5):1155-1165.
162. Nawshad A, Lagamba D, Polad A, Hay ED: Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 2005, 179(1-2):11-23.
163. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL: Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001, 12(1):27-36.
164. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS: Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 2004, 6(4):483-495.
165. Chrzanowska-Wodnicka M, Burridge K: Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol 1996, 133(6):1403-1415.
166. Yoon SH, Kim YK, Han ED, Seo YH, Kim BH, Mofrad MR: Passive control of cell locomotion using micropatterns: the effect of micropattern geometry on the migratory behavior of adherent cells. Lab Chip 2012, 12(13):2391-2402.
167. Martínez E, Engel E, Planell JA, Samitier J: Effects of artificial micro- and nano-structured surfaces on cell behaviour. Annals of Anatomy - Anatomischer Anzeiger 2009, 191(1):126-135.
168. Teixeira AI, McKie GA, Foley JD, Bertics PJ, Nealey PF, Murphy CJ: The effect of environmental factors on the response of human corneal epithelial cells to nanoscale substrate topography. Biomaterials 2006, 27(21):3945-3954.
169. Wood A: Contact guidance on microfabricated substrata: the response of teleost fin mesenchyme cells to repeating topographical patterns. Journal of cell science 1988, 90(4):667-681.
170. Biela SA, Su Y, Spatz JP, Kemkemer R: Different sensitivity of human endothelial cells, smooth muscle cells and fibroblasts to topography in the nano-micro range. Acta Biomater 2009, 5(7):2460-2466.
171. Barnhart EL, Lee KC, Keren K, Mogilner A, Theriot JA: An adhesion-dependent switch between mechanisms that determine motile cell shape. PLoS Biol 2011, 9(5):e1001059.
172. Thomson S, Petti F, Sujka-Kwok I, Mercado P, Bean J, Monaghan M, Seymour SL, Argast GM, Epstein DM, Haley JD: A systems view of epithelial-mesenchymal transition signaling states. Clin Exp Metastasis, 28(2):137-155.
173. Raiser DM, Kim CF: Commentary: Sca-1 and Cells of the Lung: A matter of Different Sorts. Stem Cells 2009, 27(3):606-611.
174. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M et al: Molecular definition of breast tumor heterogeneity. Cancer Cell 2007, 11(3):259-273.
175. Batts TD, Machado HL, Zhang Y, Creighton CJ, Li Y, Rosen JM: Stem cell antigen-1 (sca-1) regulates mammary tumor development and cell migration. PLoS One 2011, 6(11):e27841.
176. Jaggupilli A, Elkord E: Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin Dev Immunol 2012, 2012:708036.
177. Rosenbluth MJ, Lam WA, Fletcher DA: Force microscopy of nonadherent cells: a comparison of leukemia cell deformability. Biophys J 2006, 90(8):2994-3003.
178. Cross SE, Jin YS, Rao J, Gimzewski JK: Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol 2007, 2(12):780-783.
179. Lekka M, Laidler P, Gil D, Lekki J, Stachura Z, Hrynkiewicz AZ: Elasticity of normal and cancerous human bladder cells studied by scanning force microscopy. Eur Biophys J 1999, 28(4):312-316.
180. Ward KA, Li WI, Zimmer S, Davis T: Viscoelastic properties of transformed cells: role in tumor cell progression and metastasis formation. Biorheology 1991, 28(3-4):301-313.
181. Lam WA, Rosenbluth MJ, Fletcher DA: Chemotherapy exposure increases leukemia cell stiffness. Blood 2007, 109(8):3505-3508.
182. Guck J, Schinkinger S, Lincoln B, Wottawah F, Ebert S, Romeyke M, Lenz D, Erickson HM, Ananthakrishnan R, Mitchell D et al: Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys J 2005, 88(5):3689-3698.
183. Rosel D, Brabek J, Tolde O, Mierke CT, Zitterbart DP, Raupach C, Bicanova K, Kollmannsberger P, Pankova D, Vesely P et al: Up-regulation of Rho/ROCK signaling in sarcoma cells drives invasion and increased generation of protrusive forces. Mol Cancer Res 2008, 6(9):1410-1420.
184. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J: Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 2008, 68(4):989-997.
185. Basu S, Campbell HM, Dittel BN, Ray A: Purification of specific cell population by fluorescence activated cell sorting (FACS). J Vis Exp 2010(41).
186. Mathur AB, Collinsworth AM, Reichert WM, Kraus WE, Truskey GA: Endothelial, cardiac muscle and skeletal muscle exhibit different viscous and elastic properties as determined by atomic force microscopy. J Biomech 2001, 34(12):1545-1553.
187. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D et al: Tensional homeostasis and the malignant phenotype. Cancer Cell 2005, 8(3):241-254.
188. Zhong C, Kinch MS, Burridge K: Rho-stimulated contractility contributes to the fibroblastic phenotype of Ras-transformed epithelial cells. Mol Biol Cell 1997, 8(11):2329-2344.
189. Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, Kessler O, Cohen T, Resnick M, Neeman M et al: Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res 2003, 63(7):1657-1666.
190. Bruno A, Pagani A, Magnani E, Rossi T, Noonan DM, Cantelmo AR, Albini A: Inflammatory angiogenesis and the tumor microenvironment as targets for cancer therapy and prevention. Cancer Treat Res 2014, 159:401-426.
191. Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, Meyer-Schaller N, Cornille K, Hopfer U, Bentires-Alj M et al: VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res 2014, in press.
192. Mierke CT: Cancer cells regulate biomechanical properties of human microvascular endothelial cells. J Biol Chem 2011, 286(46):40025-40037.
193. Lafleur MA, Drew AF, de Sousa EL, Blick T, Bills M, Walker EC, Williams ED, Waltham M, Thompson EW: Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13. Int J Cancer 2005, 114(4):544-554.
194. Bremnes RM, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, Camps C, Marinez I, Busund LT: The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 2011, 6(1):209-217.
195. Bierie B, Moses HL: Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006, 6(7):506-520.
196. Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M, Forrester E, Yang L, Wagner KU, Moses HL: Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res 2008, 68(6):1809-1819.
197. Kessenbrock K, Plaks V, Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 141(1):52-67.
198. Dasgupta S, Bhattacharya-Chatterjee M, O'Malley BW, Jr., Chatterjee SK: Tumor metastasis in an orthotopic murine model of head and neck cancer: possible role of TGF-beta 1 secreted by the tumor cells. J Cell Biochem 2006, 97(5):1036-1051.
199. Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J et al: Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002, 109(12):1607-1615.
200. Lu SL, Reh D, Li AG, Woods J, Corless CL, Kulesz-Martin M, Wang XJ: Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res 2004, 64(13):4405-4410.
201. Halder SK, Beauchamp RD, Datta PK: A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia 2005, 7(5):509-521.
202. Alshaker HA, Matalka KZ: IFN-gamma, IL-17 and TGF-beta involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors. Cancer Cell Int, 11:33.
203. Van Themsche C, Mathieu I, Parent S, Asselin E: Transforming growth factor-beta3 increases the invasiveness of endometrial carcinoma cells through phosphatidylinositol 3-kinase-dependent up-regulation of X-linked inhibitor of apoptosis and protein kinase c-dependent induction of matrix metalloproteinase-9. J Biol Chem 2007, 282(7):4794-4802.
204. Walker L, Millena AC, Strong N, Khan SA: Expression of TGFbeta3 and its effects on migratory and invasive behavior of prostate cancer cells: involvement of PI3-kinase/AKT signaling pathway. Clin Exp Metastasis.
205. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, Stanford J, Cook RS, Arteaga CL: TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 2013, 123(3):1348-1358.
206. Derynck R, Akhurst RJ, Balmain A: TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001, 29(2):117-129.
207. Cheng JC, Auersperg N, Leung CK: TGF-Beta Induces Serous Borderline Ovarian Tumor Cell Invasion by Activating EMT but Triggers Apoptosis in Low-Grade Serous Ovarian Carcinoma Cells. Plos One 2012, 7(8):9.
208. Lehar J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, Rickles RJ, Short GF, 3rd, Staunton JE, Jin X et al: Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol 2009, 27(7):659-666.
209. Yin C, Li X, Wu Q, Wang JL, Lin XF: Multidrug nanoparticles based on novel random copolymer containing cytarabine and fluorodeoxyuridine. J Colloid Interface Sci, 349(1):153-158.
210. Nasongkla N, Shuai X, Ai H, Weinberg BD, Pink J, Boothman DA, Gao J: cRGD-functionalized polymer micelles for targeted doxorubicin delivery. Angew Chem Int Ed Engl 2004, 43(46):6323-6327.
211. You J, Zhang G, Li C: Exceptionally high payload of doxorubicin in hollow gold nanospheres for near-infrared light-triggered drug release. ACS Nano, 4(2):1033-1041.
212. Huang YC, Arham M, Jan JS: Bioactive vesicles from saccharide- and hexanoyl-modified poly(L-lysine) copolypeptides and evaluation of the cross-linked vesicles as carriers of doxorubicin for controlled drug release. European Polymer Journal 2013, 49(3):726-737.
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